Enzymes present in various tissues, including skin, function in the metabolism of drugs and environmental chemicals. The major site of such metabolism is in the liver; however, skin is one of the largest body organs and functions as a major interface with the environment. Drug-metabolizing enzyme activity in the skin may therefore be an important determinant of the biotransformation of environmental chemicals. The effect of skin applications of typical inducers of hepatic drug metabolism such as phenobarbital (PB), 3-methylcholanthrene (3-MC) and a polychlorinated-biphenyl (PCB), Aroclor 1254, on cutaneous drug metabolizing enzymes in rats will be studied. The enzyme aryl hydrocarbon hydroxylase (AHH) will be used as a prototype and it is planned to determine the tissue and subcellular localization of cutaneous AHH and to develop techniques to accurately quantitate the heme protein cytochrome P-450 in the skin. In addition, cutaneous ethylmorphine N-demethylase and aniline hydroxylase activity will be evaluated. The effects of selected cutaneous doses of PB, 3-MC, and the PCB on enzymes in skin and other tissues including liver, kidney, lungs and gastrointestinal tract will be compared to ascertain the relative importance of skin as a site of drug metabolism and as a portal of entry for environmental inducing agents. The effects of oral and systemic administration of the chemicals on enzyme activity in the skin will be studied to determine the cutaneous enzyme induction response following non-cutaneous exposure to such agents. Using skin AHH preparations, it is planned to assess the possibility that inducible cutaneous AHH may be related to the activation of carcinogens into mutagens and to the binding of carcinogens to DNA. The Ames tester strains of Salmonella typhimurium will be used for mutagenesis studies; calf-thymus DNA in vitro, and skin (epidermal) DNA in vivo will be used for the assessment of AHH-enhanced binding of carcinogens to this macromolecule. These studies are designed to evaluate the metabolic response of the skin to environmental agents, and to assess the role of cutaneous enzymes in the activation of carcinogens to mutagens and in the binding of carcinogens to DNA.